Abstract Individuals with Down syndrome (DS) are predisposed to OSAS due to craniofacial features (midface hypoplasia, glossoptosis) and studies have shown that the prevalence of OSAS in this population is markedly increased compared to that of typically developing children. Adenotonsillectomy (AT) is considered first-line treatment for childhood OSAS. However, OSAS resolves in only a portion of children with DS after AT. In fact, many children with DS are referred for positive airway pressure (PAP) therapy initiation due to persistent OSAS after AT, and PAP appears to be an important feature of the experience of living with DS. PAP has been shown to be highly effective at treating OSAS and improve OSAS-associated neurobehavioral symptoms, such as quality of life, behavior, mood, daytime sleepiness and school performance. However, PAP as a treatment for OSAS has not been well-studied in children with DS. Furthermore, patient/family reported outcomes are an important knowledge gap long overdue in this population. Therefore, we propose to leverage the HEalthy SLeeP for Children with Down Syndrome (HELP-DS, U01HL125295-S1 and U01HL123507-S1) infrastructure and conduct in two HELP-DS sites (Philadelphia and Cincinnati) a mixed methods study during the R61 phase of the award that will inform the randomized controlled trial proposed during the R33 part of the award. Families of children with DS and OSAS who are already being treated with PAP will be interviewed to identify family-relevant outcomes as these may differ from healthcare providers-relevant outcomes, and inform healthcare providers about family-relevant determinants of PAP adherence. During the R33 phase of the award, we aim at recruiting 86 children with DS and OSAS at 2 sites, aged 6-18 years, referred to PAP initiation for the treatment of OSAS. Participants will be randomized to a 6-month intensive behavioral intervention (INT) to improve PAP adherence vs standard clinical care (CON) and undergo standardized evaluations of quality of life, behavior, attention, family-relevant outcomes identified during the R61 phase, PAP adherence, and health care utilization at baseline, 6, and 12 months. This rigorous design and comprehensive study will resolve existing uncertainties on initial management approaches for children with DS and OSAS treated with PAP by addressing critical issues: a) assess outcomes of importance to families, b) determine the efficacy of INT vs CON in promoting PAP adherence, c) elucidate which factors mediate or moderate adherence to PAP in children with DS and OSAS, d) determine the effect of PAP use on neurobehavioral and family-relevant outcomes, quality of life, and healthcare utilization.